Enhanced mechanical heterogeneity of cell collectives due to temporal fluctuations in cell elasticity

TL;DR

This study explores how temporal fluctuations in cell stiffness influence the spatial organization and growth dynamics of tumor cell collectives, revealing that heterogeneity in cell elasticity enhances tumor progression.

Contribution

It introduces a minimal 3D model demonstrating that fluctuations in cell stiffness lead to spatial heterogeneity and increased tumor growth, a novel insight into tumor biomechanics.

Findings

Spatial heterogeneity with stiffer cores and softer peripheries emerges in tumor spheroids.

Fluctuations in cell stiffness promote tumor growth and cell dynamics.

Enhanced heterogeneity correlates with increased tumor progression.

Abstract

Cells are dynamic systems characterized by temporal variations in biophysical properties such as stiffness and contractility. Recent studies show that the recruitment and release of actin filaments into and out of the cell cortex - a network of proteins underneath the cell membrane - leads to cell stiffening prior to division and softening immediately afterward. In three-dimensional (3D) cell collectives, it is unclear whether the stiffness change during division at the single-cell scale controls the spatial structure and dynamics at the multicellular scale. This is an important question to understand as cell stiffness variations play an important role in tissue spatial organization and cancer progression. Using a minimal 3D model incorporating cell birth, death, and cell-to-cell elastic and adhesive interactions, we investigate the effect of mechanical heterogeneity - variations in individual cell stiffnesses that make up the tumor cell collective - on tumor spatial organization and cell dynamics. We discover that spatial mechanical heterogeneity characterized by a spheroid core composed of stiffer cells and softer cells in the periphery emerge within dense 3D cell collectives, which may be a general feature of multicellular tumor growth. We show that heightened spatial mechanical heterogeneity enhances single-cell dynamics and volumetric tumor growth driven by fluctuations in cell elasticity. Our results could have important implications for understanding how spatiotemporal variations in single-cell stiffness determine tumor growth and spread.